This invention relates to a hydrogel-forming system with hydrophobic and hydrophilic components which forms a hydrogel with a crosslinked polymer network structure, hydrogels therefrom entrapping therapeutic agents and vascular stents with coating comprising said hydrogel entrapping therapeutic agent.
Up until recently, hydrogels have been based only on hydrophilic components. The need for a new class of hydrogels having both hydrophilic and hydrophobic segments has been highlighted by the increasingly available new therapeutic proteins, peptides and oligonucleotides that are mainly of a hydrophobic nature because it is difficult to homogeneously disperse hydrophobic drugs or hydrophobic bioactive molecules within a totally hydrophilic polymer hydrogel to achieve predictable drug release profiles. Moreover, apart from the need to more effectively handle hydrophobic drugs, hydrogels with hydrophobic and hydrophilic components have the advantages over totally hydrophilic-based hydrogels in maintaining structural integrity for relatively longer periods of time and in mechanical strength.
Despite the need for and advantages of hydrogels having both hydrophilic and hydrophobic components, there are only a few reported studies on these. All these studies rely on either synthesis of copolymers from appropriate monomers without crosslinking or rely on the physical blending of hydrophobic and hydrophilic polymers. The synthesis of copolymer involved copolymeiization of polylactide oligomer and polyethylene glycol and did not provide a hydrogel with a crosslinked polymer network or hydrophobic property. The method of physical blending has the major flaw of poor integration between hydrophilic and hydrophobic components, i.e., lack of uniformity throughout the composition.
The invention herein provides a hydrogel with both hydrophobic and hydrophilic components without relying on the copolymer approach or physical blending but instead relies on hydrophobic and hydrophilic components which are convertible into a one phase crosslinked polymer network structure by free radical polymerization.
In one embodiment herein, denoted the first embodiment, the invention is directed to a hydrogel-forming system which comprises from 0.01 to 99.99% by weight of (A) a hydrophobic macromer with unsaturated group, e.g., vinyl group, terminated ends and from 99.99 to 0.01% by weight of (B) a hydrophilic polymer which is a polysaccharide containing hydroxyl groups which are reacted with unsaturated group, e.g., vinyl group, introducing compound; wherein the total of the percentages of (A) and (B) is 100%.
Preferably, the hydrophobic macromer is biodegradable and very preferably is prepared by reacting diol obtained by converting hydroxy of terminal carboxylic acid group of poly(lactic acid) to aminoethanol group, with unsaturated group introducing compound.
Preferably, the hydrophilic polymer is dextran wherein one or more hydroxyls in a glucose unit of the dextran is (are) reacted with unsaturated group introducing compound.
In one case, the hydrophilic polymer can be dextran-maleic acid monoester as described in WO 00/12619 which is incorporated herein by reference.
In another embodiment, denoted the second embodiment, a hydrogel preferably a biodegradable hydrogel, is formed by the free radical polymerization, preferably by photocrosslinking, of the hydrogel-forming system of the embodiment described above, which has a three dimensional crosslinked polymer network structure. In one alternative of this embodiment, a drug of weight average molecular weight ranging from 200 to 1,000, as exemplified by indomethacin, is entrapped in the three dimensional crosslinked polymer network for controlled release therefrom. In another alternative of this embodiment, a macromolecule of weight average molecular weight ranging from 1,000 to 100,000, e.g., a polypeptide, as exemplified by insulin, is entrapped in the three dimensional crosslnked polymer network for controlled release therefrom. In still another alternative of this embodiment, a synthetic or natural polymer, e.g., of weight average molecular weight ranging from 10,000 to 500,000, is entrapped in the three dimensional crosslinked polymer network for controlled release therefrom.
One variation of the second embodiment is directed to a hydrogel which has a three dimensional crosslinked polymer network containing hydrophobic and hydrophilic components having entrapped in the three dimensional structure bioactive agent selected from the group consisting of drugs or biologics of weight average molecular weight ranging from 200 to 1,000, macromolecules of weight average molecular weight ranging from 1,000 to 100,000 and synthetic or natural polymers of weight average molecular weight ranging from 10,000 to 500,000, said hydrogel being formed by the free radical polymerization of a hydrogel-forming system which comprises from 0.01 to 99.99% by weight of (A) a hydrophobic macromer with unsaturated group terminated ends, and from 99.99 to 0.01% by weight of (B) a hydrophilic polymer which is a polysaccharide containing hydroxy groups which are reacted with unsaturated group introducing compound, the total of the percentages of (A) and (B) being 100%. In a preferred case, the agent is a therapeutic agent for treating, postponing or preventing disorder selected from the group consisting of coronary artery disease, inflammation, restenosis and stent rejection and is present in a therapeutically effective amount.
In another embodiment, denoted the third embodiment, a cardiac stent contains a coating comprising the hydrogel containing entrapped agent as described in the paragraph directly above this one.
The term xe2x80x9chydrogelxe2x80x9d is used herein to mean a polymeric material which exhibits the ability to swell in water and to retain a significant portion of water within its structure without dissolving.
A biodegradable hydrogel herein is a hydrogel formed from a hydrogel forming system containing at least one biodegradable component, i.e., component which is degraded by water and/or by enzymes found in nature.
The term xe2x80x9ccrosslinked polymer network structurexe2x80x9d is used herein to mean an interconnected structure where crosslinks are formed between hydrophobic molecules, between hydrophilic molecules and between hydrophobic molecules and hydrophilic molecules.
The term xe2x80x9cphotocrosslinkingxe2x80x9d is used herein to mean causing vinyl bonds to break and form crosslinks by the application of radiant energy.
The term xe2x80x9cmacromerxe2x80x9d is used herein to mean monomer having a weight average molecular weight ranging from 500 to 80,000.
The term xe2x80x9cunsaturated group introducing compoundxe2x80x9d is used herein to mean compound that reacts with hydroxyl group and provides a pendant or end group containing an unsaturated group, e.g., a pendant group with a vinyl group at its end.
The weight average molecular weights herein are determined by gel permeation chromatography.
The number average molecular weights herein are determined by gel permeation chromatography.